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Liquid or soft-gel levothyroxine vs tablet levothyroxine in athyreotic adults after total thyroidectomy: Systematic review and meta-analysis
Muhammad Farhan, Tirath Patel, Mohammed Al-Hadi Naseer Obais, Hassan Taslimi, Maira Hanif, Kawish Khalid, Ali Qaqour, Juman Waisi, Hafsa Khalid, Aalaa Hasan Abdulla Abbas Husain, Ruba Hammouda, Safi Ullah Khan, Bhumi Daishik Patel, Nana Sardarova, Ayoola Awosika
Muhammad Farhan, Hassan Taslimi, Maira Hanif, Kawish Khalid, Ali Qaqour, Juman Waisi, Hafsa Khalid, Aalaa Hasan Abdulla Abbas Husain, Department of Medicine, College of Medicine, Ajman University, Ajman 6263, United Arab Emirates
Tirath Patel, Department of Medicine, Trinity Medical Sciences University School of Medicine, Kingstown VC0100, Saint George, Saint Vincent and the Grenadines
Mohammed Al-Hadi Naseer Obais, Department of Internal Medicine, Ajman University, Ajman 6263, United Arab Emirates
Ruba Hammouda, Department of Medicine, Ain Shams University, Cairo 11511, Al Qāhirah, Egypt
Safi Ullah Khan, Department of Medicine, Bahria University Medical and Dental College, Karachi 72500, Sindh, Pakistan
Bhumi Daishik Patel, Department of Internal Medicine, Windsor University School of Medicine, St Kitts 01000, Saint Kitts and Nevis
Nana Sardarova, Department of Internal Medicine, Henry Ford Warren Hospital, Warren, MI 48093, United States
Ayoola Awosika, Department of Family and Community Medicine, University of Illinois College of Medicine Peoria, Bloomington, IL 61601, United States
Author contributions: Farhan M, Patel T, Obais MAHN, Taslimi H, Khalid K, Qaqour A, Waisi J, Khalid H, and Awosika A contributed to conceptualization and overall coordination; Farhan M, Patel T, Obais MAHN, Taslimi H, Hanif M, Khalid K, Qaqour A, Waisi J, Khalid H, Abbas Husain AHA, Hammouda R, Khan SU, Patel BD, Sardarova N, and Awosika A contributed to literature search, evidence acquisition and data extraction, interpretation and synthesis of evidence; Farhan M, Patel T, Obais MAHN, Hanif M, Khalid H, Abbas Husain AHA, Hammouda R, Khan SU, Patel BD, Sardarova N, and Awosika A contributed to original draft preparation; Farhan M, Taslimi H, Hanif M, Khalid K, Qaqour A, Waisi J, Abbas Husain AHA, Hammouda R, Khan SU, Patel BD, Sardarova N, and Awosika A reviewed and edited the manuscript; Awosika A contributed to supervision and senior oversight. All authors agreed and are accountable for all aspects of the work in ensuring accuracy/integrity of all sections of the manuscript, and everyone have given final approval of the manuscript version to be published.
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Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Corresponding author: Ayoola Awosika, MD, Department of Family and Community Medicine, University of Illinois College of Medicine Peoria, 1 Illini Drive, Bloomington, IL 61601, United States.
ayoolaawosika@yahoo.com
Received: February 5, 2026
Revised: February 23, 2026
Accepted: April 1, 2026
Published online: June 6, 2026
Processing time: 108 Days and 6.7 Hours
BACKGROUND
Achieving stable thyroid hormone replacement after total thyroidectomy is challenging owing to the variability in levothyroxine (LT4) absorption. Newer liquid and soft-gel formulations may offer improved bioavailability compared to conventional tablets, but their benefits in thyroidectomized patients remain uncertain.
AIM
To compare the effectiveness of liquid and soft-gel LT4 with tablet LT4 in athyreotic adults following total thyroidectomy.
METHODS
A systematic review and meta-analysis were conducted according to the PRISMA 2020 guidelines. The MEDLINE, EMBASE, CENTRAL, and Scopus databases were searched from inception to January 1, 2026. Randomized controlled trials and cohort studies enrolling adults after total thyroidectomy were included. The primary outcome was serum thyroid-stimulating hormone level. Secondary outcomes included circulating total thyroxine and triiodothyronine levels. Standardized mean differences (SMD) with 95% confidence intervals (CIs) were pooled using a random effects model. Subgroup analyses were performed based on the disease etiology, malabsorption status, and study design.
RESULTS
Nine studies comprising 1115 participants were included. Liquid or soft-gel LT4 was associated with significantly lower thyroid-stimulating hormone level compared with tablets (SMD: -0.91; 95%CI: -1.52 to -0.30; P = 0.003), with high heterogeneity (I2 = 95%). Subgroup analysis showed a significant effect in patients treated for benign disease but not in those with differentiated thyroid cancer. A significant benefit was observed in patients without documented malabsorption, whereas no statistically significant difference was found in those with malabsorption. Liquid LT4 resulted in higher total thyroxine (SMD: 0.34; 95%CI: 0.15-0.52) and triiodothyronine levels (SMD: 0.25; 95%CI: 0.06-0.44), with no heterogeneity.
CONCLUSION
While observational data suggest improved control, this benefit was not replicated in randomized controlled trials, highlighting the need for further high-quality trials. Routine substitution for all patients was not supported, highlighting the need for individualized LT4 therapy.
Core Tip: Levothyroxine (LT4) is one of the most widely prescribed medications for hypothyroidism globally; however, its narrow therapeutic index requires careful dose individualization to avoid the risks of iatrogenic hyperthyroidism or hypothyroidism. In this systematic review and meta-analysis of athyreotic adults following total thyroidectomy, liquid or soft-gel LT4 was associated with significantly lower thyroid-stimulating hormone levels and modest but consistent increases in circulating total thyroxine and triiodothyronine levels compared with tablet formulations. These findings support a personalized approach to LT4 therapy, rather than the routine substitution of formulations, in all thyroidectomized patients.
